• Type 1 diabetes and type 2 diabetes
• Beta cell biology, islet amyloid, amylin, insulin, prohormone processing, apoptosis, hormone secretion, transgenic mice, islet transplantation, autoantigens, histology

Islet amyloid and type 2 diabetes
Islet amyloid is composed primarily of a beta cell peptide named islet amyloid polypeptide (IAPP or amylin), which accumulates in the pancreatic islets of persons with type 2 diabetes and kills the insulin-producing beta cells. My laboratory is trying to understand why IAPP aggregates to form these toxic deposits and how these deposits kill beta cells, in the hope that we may be able to find ways to inhibit these processes. We have elucidated the pathway by which the IAPP precursor peptide (proIAPP) is likely processed to produce mature IAPP in beta cells, and have proposed a mechanism by which defective processing of proIAPP may lead to islet amyloid formation. We have also begun to dissect the molecular pathway by which amyloid induces beta cell apoptosis. Funding for this research is from CIHR and the Canadian Diabetes Association.

Immune-mediated beta cell death in type 1 diabetes
In type 1 diabetes, beta cell death is caused by the action of pro-inflammatory cytokines as well as autoreactive T lymphocytes that specifically target beta cells for destruction. In collaboration with Dr. Rusung Tan and others, we are trying to elucidate the mechanisms by which cytokines and T cells, in particular CD8+ cytotoxic T lymphocytes (CTL), kill beta cells with a long-term aim of blocking these processes as a way of preventing disease. As one approach we are actively trying to identify novel beta cell proteins (epitopes) that CTL recognize on the surface of beta cells, in both new-onset diabetic children and in the non-obese diabetic (NOD) mouse model of type 1 diabetes. Identification of the beta cell autoepitopes targeted by CTL in type 1 diabetes may lead to new tools for disease prediction and prevention. Funding for this research is from CIHR and the Juvenile Diabetes Research Foundation.

Pancreatic islet transplantation
Transplantation of pancreatic islets as a means of beta cell replacement in patients with type 1 diabetes has shown tremendous promise, but is still limited by uncertainty regarding the long-term survival of transplanted beta cells and the need for lifelong immunosuppression. Apoptotic death of beta cells occurs during islet isolation, culture, and transplantation, as well as during the immune attack on transplanted islet cells. We are trying to devise novel ways to protect transplanted beta cells in order to enhance the long-term success of islet transplants. For example, we have used viral vectors to transfer genes that inhibit apoptotic cell death and found that it protects transplanted islets from allograft rejection. We are also testing whether inhibition of islet amyloid formation enhances survival of transplanted islets. This research is funded by the Juvenile Diabetes Research Foundation, BC's Children's Hospital Foundation, and Neurochem Inc.

Montane J, Bischoff L, Soukhatcheva G, Dai DL, Hardenberg G, Levings MK, Orban PC, Kieffer TJ, Tan R, Verchere CB.: Prevention of murine autoimmune diabetes by CCL22-mediated Treg recruitment to the pancreatic islets. J Clin Invest. 2011 Jul 1. pii: 43048. doi: 10.1172/JCI43048. [Epub ahead of print] PMID: 21737880

Wang X, Hao J, Metzger DL, Mui A, Ao Z, Verchere CB, Chen L, Ou D, Warnock GL.: Local expression of b7-h4 by recombinant adenovirus transduction in mouse islets prolongs allograft survival. Transplantation. 2009 Feb 27;87(4):482-90.

Warnock GL, Thompson DM, Meloche RM, Shapiro RJ, Ao Z, Keown P, Johnson JD, Verchere CB, Partovi N, Begg IS, Fung M, Kozak SE, Tong SO, Alghofaili KM, Harris C.: A multi-year analysis of islet transplantation compared with intensive medical therapy on progression of complications in type 1 diabetes. Transplantation. 2008 Dec 27;86(12):1762-6.

Marzban L, Tomas A, Becker TC, Rosenberg L, Oberholzer J, Fraser PE, Halban PA, Verchere CB.: Small interfering RNA-mediated suppression of proislet amyloid polypeptide expression inhibits islet amyloid formation and enhances survival of human islets in culture. Diabetes. 2008 Nov;57(11):3045-55.

Meng F, Marek P, Potter KJ, Verchere CB, Raleigh DP.: Rifampicin does not prevent amyloid fibril formation by human islet amyloid polypeptide but does inhibit fibril thioflavin-T interactions: implications for mechanistic studies of beta-cell death. Biochemistry. 2008 Jun 3;47(22):6016-24.

Trudeau JD, Kelly-Smith C, Verchere CB, Elliott JF, Dutz JP, Finegood DT, Santamaria P, Tan R: Prediction of spontaneous autoimmune diabetes by quantification of autoreactive T cells in peripheral blood. J Clin Invest 111:217-23, 2003.

Vidal J, Verchere CB, Andrikopoulos S, Wang F, Hull RL, Cnop M, Olin KL, LeBoeuf RC, O'Brien KD, Chait A, Kahn SE: The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice. Diabetologia 46:71-79, 2003.

Wang J, Xu J, Finnerty J, Furuta M, Steiner DF, Verchere CB: The prohormone convertase enzyme 2 (PC2) is essential for processing of pro-islet amyloid polypeptide at the N-terminal cleavage site. Diabetes 50:534-539, 2001.

Park K, Verchere CB Identification of a heparin-binding domain in the N-terminal cleavage site of pro-islet amyloid polypeptide: implications for islet amyloid formation. J Biol Chem 276:16611-16616, 2001.

Verchere CB, D'Alessio DA, Prigeon RL, Hull RL, Kahn SE: The constitutive secretory pathway is a major route for islet amyloid polypeptide release in neonatal but not adult rat islet cells. Diabetes 49:1477-1484, 2000.

Kahn SE, Andrikopoulos S, Verchere CB: Islet amyloid: a long recognized but under appreciated pathology of type 2 diabetes mellitus. Diabetes 48:241-253, 1999.

Irminger J-C, Verchere CB, Meyer K, Halban PA: Proinsulin targeting to the regulated pathway is not impaired in carboxypeptidase E-deficient Cpefat/Cpefat mice. J Biol Chem 272:27532-27534, 1997.

Deeg M, Verchere CB: Regulation of GPI-specific phospholipase D secretion from beta TC3 cells. Endocrinology 138: 819-826, 1997.

Verchere CB, D'Alessio DA, Palmiter RD, Weir GC, Bonner-Weir S, Baskin DG, Kahn SE: Islet amyloid formation associated with hyperglycemia in transgenic mice with beta cell expression of human islet amyloid polypeptide. Proc Natl Acad Sci USA 93:3492-3496, 1996.

Verchere CB, Paoletta M, Neerman-Arbez M, Rose K, Gingerich RL, Kahn SE, Halban PA: Des-(27-31)C-peptide: a novel secretory product of the rat pancreatic beta cell produced by truncation of proinsulin connecting peptide in secretory granules. J Biol Chem 271:27475-27481,1996.

Queen Elizabeth II Diamond Jubilee Medal

Best overall abstract, World Artificial-Organ, Implants and Transplantation Society (WAITS) Symposium, Ottawa - 2001

Outstanding Young Alumnus Award, University of British Columbia - 2000

Research and Discovery Award, Department of Pathology & Laboratory Medicine, University of British Columbia - 1999

Medical Research Council of Canada Scholarship / Canadian Institutes of Health Research New Investigator Award - 1998

Albert Renold Fellowship (European Association for the Study of Diabetes) - 1996

Medical Research Council of Canada Post-Doctoral Fellowship - 1993

Juvenile Diabetes Research Foundation Post-Doctoral Fellowship - 1992

Kathy Hsu, MD - Postdoctoral fellow and graduate (MSc) student
Mike Kennedy, BSc - Graduate (PhD) student
Lucy Marzban, MD, PhD - Postdoctoral fellow (BCRICWH postdoctoral fellowship)
Kirily Park, BSc - Graduate (PhD) student (Graduate studentships from CIHR and the Killam Foundation)
Annette Plesner, PhD - Postdoctoral fellow (Eli Lilly / European Association for the Study of Diabetes postdoctoral fellowship)
Dina Panagiotopoulos, MD - Postdoctoral fellow (Research fellowship from Eli Lilly and the Canadian Pediatric Endocrine Group)
Galina Soukhatcheva, BSc - Technician
Genny Trigo, BSc, MSc - Technician and laboratory manager